The genes responsible for the majority of familial colorectal cancer cases have not yet been identified. Myriad Genetics, Inc. has at its disposal many extended, high risk colon cancer pedigrees that are not linked to any of the identified colon cancer predisposition syndromes, familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC). These pedigrees will allow identification of novel genes involved in predisposition to colon carcinogenesis. We propose to develop and perform a genomic search on these pedigrees in order to discover new colon cancer predisposition genes. Specifically, in SBTR Phase I we propose generation and analysis of a full genomic search on a subset of the high-risk colorectal cancer pedigrees already sampled, and the further development of colon cancer pedigrees. Linkage analysis will identify regions likely to contain colon cancer predisposition genes. Further region specific genotyping and positional cloning and pedigree extension will be outlined in an SBIR Phase II proposal. Any novel mutations found will be used in the development of cancer diagnostics, while the genes and related pathways will be scrutinized as targets for drug discovery. The study of Utah high-risk pedigrees provides a proven method for the identification of novel pharmaceutical targets involved in carcinogenesis. PROPOSED COMMERCIAL APPLICATIONS: The market for both cancer diagnostics & therapeutics is tremendous. Approximately 15% of colon cancer diagnoses involve a genetic component. We expect to identify several colon cancer genes with mutations that add to our cancer diagnostics division. These genes and related pathways will also be scrutinized for drug discovery.